Kinetic Isotope Effects The Study of Organometallic Reaction Mechanisms Alexander J. Kendall – D.R. Tyler Group Meeting – 7/23/2014 Gómez-Gallego, M.; Sierra, M. A. Chem. Rev. 2011, 111, 4857-4963. Outline • General physical organic mechanism investigation • Kinetic isotope effect (KIE) • Origins of the effect • Types of KIEs • Primary • Secondary • Equilibrium • Solvent • Quantum tunneling • Steric • Magnitude factors in KIE • Organometallic studies • Early work • Misleading results • Modern example • Conclusions Physical Organic Mechanistic Determination • Experiments designed to “unlock the secrets of organic reaction mechanisms” • Commonly used experiments • Kinetic studies • Reactivity trends • Stereochemical studies • Isotopic tracers • Substituent effects • Radical clocks • Crossover experiments • Kinetic isotope effects Blum, S. A.; Tan, K. L.; Bergman, R. G. J. Org. Chem. 2003, 68, 4127-4137. Goerisch, H. Biochemistry, 1978, 17, 3700. Physical Organic Mechanistic Determination • Law of Mass-Action (1864) • experimental determination of reaction rates • rate laws and rate constants can be derived 푛 푚 • Kinetic studies • 푟푎푡푒 = 푘[퐴] [퐵] • Reactivity trends • Arrhenius Equation (1889) • Stereochemical studies • 푘 = A푒−퐸푎 (푅푇) • Isotopic tracers • E = Energy/mol of kinetic barrier • Substituent effects a • Radical clocks • Eyring Equation (1935) 푘 푇 ‡ ‡ • Crossover experiments • 푘 = 퐵 (푒∆푆 푅)(푒−∆퐻 푅푇) • Kinetic isotope effects ℎ • Energy in entropy and enthalpy C.M. Guldberg; P. Waage C. M. Forhandlinger: Videnskabs-Selskabet i Christiana, 1864, 35. ; P. Waage Forhandlinger i Videnskabs- Selskabet i Christiania, 1864, 92. ; C.M. Guldberg C. M. Forhandlinger i Videnskabs-Selskabet i Christiania 1864, 111. ; Arrhenius, S.A. Z. Physik. Chem. 1889, 4, 96–116. ; Arrhenius, S.A. ibid. 1889, 4, 226–248. ; Eyring, H. J. Chem. Phys. 1935, 3, 107. Physical Organic Mechanistic Determination • Observe trends in reactivity • Intermediates can be inferred • Limits of reactivity book-end • Kinetic studies • Reactivity trends • Stereochemical studies • Isotopic tracers • Substituent effects • Radical clocks • Crossover experiments • Kinetic isotope effects Blum, S. A.; Tan, K. L.; Bergman, R. G. J. Org. Chem. 2003, 68, 4127-4137. Physical Organic Mechanistic Determination • Kinetic studies • Reactivity trends • Stereochemical studies • Isotopic tracers • Substituent effects • Radical clocks • Crossover experiments • Kinetic isotope effects Asarum teitonense Hayata Kurti, L.; Szilagyi, L.; Antus, S.; Nogradi, M. Eur. J. Org. Chem. 1999, 2579-2581. Physical Organic Mechanistic Determination • Kinetic studies • Reactivity trends • Stereochemical studies • Isotopic tracers • Substituent effects • Radical clocks • Crossover experiments • Kinetic isotope effects 2005 Nobel Prize in Chemistry Grubbs, Robert H.; Burk, Patrick L.; Carr, Dale D. J. Am. Chem. Soc. 1975, 97, 3265–3267. Physical Organic Mechanistic Determination • Kinetic studies • Reactivity trends • Stereochemical studies • Isotopic tracers • Substituent effects • Structure assignment • Radical clocks • Trap out reactive sites to prove where they were • Crossover experiments generated in-situ • Kinetic isotope effects Baran, J. R.; Hendrickson, C.; Laude, D. A.; Lagow, R. J. J. Org. Chem. 1992, 57, 3759-3760. Physical Organic Mechanistic Determination • Kinetic studies • Reactivity trends • Stereochemical studies • Hammet Equation (1937) • Isotopic tracers 퐾 • log( ) = • Substituent effects 퐾0 • Radical clocks • = substituent constant • Crossover experiments • = reaction constant • Kinetic isotope effects Hammett, Louis P. J. Am. Chem. Soc. 1937, 59, 96. Physical Organic Mechanistic Determination • Kinetic studies • Reactivity trends • Stereochemical studies • Hammet Equation (1937) • Isotopic tracers 퐾 • log( ) = • Substituent effects 퐾0 • Radical clocks • = substituent constant • Crossover experiments • = reaction constant • Kinetic isotope effects Hammett, Louis P. J. Am. Chem. Soc. 1937, 59, 96. Physical Organic Mechanistic Determination • Radical clocks • Use competing uni-molecular radical reactions as qualitative timing devices to investigate the rates of radical-molecule reactions • Kinetic studies • Reactivity trends • Stereochemical studies • Isotopic tracers • Substituent effects • Radical clocks • Crossover experiments • Kinetic isotope effects Griller, D.; Ingold, K. U. Acc. Chem. Res. 1980, 13, 317-323. Physical Organic Mechanistic Determination • Kinetic studies • Reactivity trends • Stereochemical studies • Isotopic tracers • Substituent effects • Radical clocks • Crossover experiments • Kinetic isotope effects Carroll, Felix A.; Perspectives on Structure and Mechanism in Organic Chemistry; Brooks/Cole Publishing, Pacific Grove, CA, 1998 Physical Organic Mechanistic Determination • Kinetic studies • Reactivity trends • Stereochemical studies • Isotopic tracers • Substituent effects • Radical clocks • Crossover experiments • Kinetic isotope effects Carroll, Felix A.; Perspectives on Structure and Mechanism in Organic Chemistry; Brooks/Cole Publishing, Pacific Grove, CA, 1998 Physical Organic Mechanistic Determination • Isotope effects • Same reaction mechanisms • NMR and MS compatible • Well established protocols and isotope sources • Kinetic studies • Works well for short-lived RDS intermediates • Reactivity trends • Works well for complex reaction mechanisms • Stereochemical studies • Which bonds broken/formed in RDS? • Isotopic tracers • Substituent effects “As the chemistry of the metal determines the course of the • Radical clocks reaction, the standard approaches of physical organic • Crossover experiments chemistry are sometimes of little use in the study of insights • Kinetic isotope effects of the reactions.” Blum, S. A.; Tan, K. L.; Bergman, R. G. J. Org. Chem. 2003, 68, 4127-4137. Gómez-Gallego, M.; Sierra, M. A. Chem. Rev. 2011, 111, 4857-4963. Origins of the Kinetic Isotope Effect (KIE) • All KIEs rely on a difference in zero-point energies 1 푘 • 푣 = 2휋 푚푟 • v= bond stretching vibration • k= bond force constant 푚1푚2 • 푚푟 = 푚1+푚1 Zero-Point Energy (ZpE) • The result of this mass difference: • m1= C,N,O; m2= H,D; • kH/kD ≤ 6.8 (298K) • kH = rate of reaction with hydrogen • kD = rate of reaction with deuterium • Heavy isotope effects (m2 ≠ H or D) • Much smaller effect due to mr being very close for heavy isotopes Types of Kinetic Isotope Effects • Primary isotope effect • Isotope replacement has been made in a bond that is broken in the RDS; • kH/kD >>1 Types of Kinetic Isotope Effects • Secondary isotope effect TS‡ • Isotope replacement made far from TS‡ reactive center, or in bonds that only change their hybridization in the RDS; • kH/kD ~ 1.2 (normal) • kH/kD ~ 0.8 (inverse) Ho o (∆∆EE ) (∆ED)o C-H/D bonds are not being broken during the reaction, but the carbon atoms experience an sp3 to sp2 hybridization change. Types of Kinetic Isotope Effects • Secondary isotope effect • Isotope replacement made far from TS‡ TS‡ reactive center, or in bonds that only change their hybridization in the RDS; • kH/kD ~ 1.2 (normal) • kH/kD ~ 0.8 (inverse) (∆(∆EEHH))oo (∆ED)o C-H/D bonds are not being broken during the reaction, but the carbon atoms experience an sp2 to sp3 hybridization change. Types of Kinetic Isotope Effects • Equilibrium isotope effect (a thermodynamic isotope effect) • Isotopic change affects the individual rate constants in an equilibrium, modifying Keq values 퐻 퐷 푘1 푘1 퐾푒푞 = 퐻 퐷 푘−1 푘−1 Types of Kinetic Isotope Effects • Solvent isotope effect • Kinetic or equilibrium changes observed when the isotopic substitution is made in the reaction solvent (usually H2O/D2O) • Protic solvents can interchange acidic protons for deuterium • In-situ isotope labeling • Exchangeable proton involved in the RDS = large solvent KIE • Differences in the solvation of the activated complex compared to the reactants • Hydrogen bonding of the activated complex Types of Kinetic Isotope Effects • Solvent isotope effect • Hydrogen bonding of the activated complex H-Bonding D-Bonding Steiner, T. Angew. Chem. Int. Ed. 2002, 41, 48-76. Types of Kinetic Isotope Effects • Quantum tunneling isotope effect • If the RDS involves a proton quantum tunneling, an extreme KIE is observed, albeit very rare; • kH/kD >10 • To tell if you have a tunneling proton • Tunneling is caused by wave mechanics • Low temperature reactions (cryogenic) • Large -S‡ Buncel, E.; Lee, C.C. Isotopes in Organic Chemistry. Elsevier: Amsterdam, 1977, Vol. 5. Krishtalik, L. I. Biochimica et Biophysica Acta 2000, 1458, 6–27. Types of Kinetic Isotope Effects • Steric Isotope Effect 퐻 퐷 • 푘1 푘1 = 0.88 • C-D bond shorter than C-H bond • D = smaller van der Waals radius (15% smaller than H) • D2O(s) sinks in H2O Mislow, K.; Graeve, R.; Gordon, A. J.; Wahl, G. H. J. Am. Chem. Soc. 1963, 85, 1199–1200. A. R. Ubbelohde Trans. Faraday Soc., 1936, 32, 525-529. Magnitude of the KIE • Dependent on ZpE of reactants and ZpE of transition states • All vibrations for the bonds undergoing transformation contribute to observed KIE TS‡ • kH/kD values are affected by: • Geometry of TS‡, • Degree of bond breaking in TS‡, • Degree of bond making in TS‡, and • Position of the TS‡ in the reaction coordinate (early, middle, or late TS‡) H o (∆E ) (∆ED)o Bigeleisen, J.; Wolfsberg, M. Adv. Chem. Phys. 1958, 1, 15. Magnitude of the KIE • Dependent on ZpE of reactants and ZpE of transition states • All vibrations for the bonds undergoing transformation contribute to observed KIE TS‡ • kH/kD values are affected by: • Geometry